Studies & registries

Introduction

Optimisation of general physiological conditions in the setting of an acute stroke

Treatment of an acute stroke – thrombolysis and revascularisation

Management of complications following an acute stroke

Rehabilitation – restoring as much function as possible to a patient after a stroke

Secondary prevention – avoidance of a recurrent stroke

In the acute stroke setting, Time is brain and the studies and registries in this section concentrate on how a patient should be managed on arrival at the hospital, including the advantage of treatment in a stroke unit, the evidence for thrombolysis, the benefits of rt-PA, and the importance of time.

Thrombolytic therapy for acute ischaemic stroke has been approached cautiously because there were high rates of intracerebral haemorrhage in early clinical trials. The NINDS Investigators performed a randomised, double-blind trial of intravenous recombinant tissue plasminogen activator (rt-PA) for ischaemic stroke after recent pilot studies suggested that rt-PA was beneficial when treatment was begun within three hours of the onset of stroke.

NINDS showed that:

For all stroke subtypes, treatment with intravenous rt-PA within 3 hours of the onset of ischaemic stroke improved clinical outcome at 3 months.

The greater proportion of patients were left with minimal or no deficit at 3 months after treatment with rt-PA

Treatment with rt-PA compared with placebo was not accompanied by an increase in severe disability or mortality.

Conclusion

In comparison to placebo, patients treated with rt-PA within 3 hours of an acute ischaemic stroke had approximately 30% less disability.

The efficacy of rt-PA is highest if initiated within 90 min of stroke symptom onset. However, many stroke victims do not reach a centre equipped to administer rt-PA in time, so that worldwide, <5% of acute ischaemic stroke patients are treated with rt-PA within 3 hours of stroke symptom onset.

rt-PA was approved by the EU regulatory authority EMEA in 2002 for use within 3 h of ischaemic stroke with two post-approval requirements:

All patients should be registered in the SITS internet database and entered into an observational safety study, SITS-MOST.

A randomised trial of rt-PA versus placebo should be performed, with an extended therapeutic window greater than 3 hours.

A pooled analysis of individual patient data (N=2,775) from 6 trials of i.v. rt-PA vs. placebo in 2004 showed that the effective treatment window may extend to 4.5 hours.

Objective

The objective of this double-blind, parallel-group, placebo controlled study was to evaluate the efficacy and safety of intravenous thrombolysis using rt-PA administered 3 to 4.5 hours after onset of stroke symptoms in patients with acute ischaemic stroke.

Summary of ECASS 3

Patients were eligible for inclusion if they were 18 to 80 years of age, had received a clinical diagnosis of acute ischaemic stroke, and were able to receive the study drug within 3 to 4.5 hours. A cerebral computer tomographic (CT) scan was required before randomisation to exclude patients who had an intracranial haemorrhage or major ischaemic infarction.

821 patients in 19 European countries were enrolled.

Out of the randomised groups, 375 patients were treated with 0.9 mg intravenous rt-PA per kg body weight (with an upper, limit of 90 mg) and 355 patients received placebo.

Primary endpoint was disability at 90 days, dichotomised as a favourable outcome (a score of 0 or 1 on the modified Rankin scale).

In this study, a 52.4% favourable outcome for patients in the rt-PA group compared to 45.2% in the placebo group was reported (odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; relative risk, 1.16; 95% CI, 1.01 to 1.34; p=0.04).

The overall rate of symptomatic intracranial haemorrhage (sICH) was low with rt-PA (2.4%) and comparable to the 3-hour time window.

Even though the rate of intracranial haemorrhage was higher than with placebo (27% vs. 17.6%; p=0.001; for sICH, 2.4% vs. 0.2%; p=0.008), there was no significant difference in the rate of mortality or other severe adverse events (7.7% and 8.4%, respectively; p=0.68).

These findings are consistent with the results from other randomised, controlled trials of thrombolysis in patients with acute ischaemic stroke.

Conclusion

While the trial outcome showed that rt-PA is safe and effective up to 4.5 hours after the onset of acute ischaemic stroke symptoms, patients should be treated as early as possible to maximise the benefit.

Having more time does not mean we should be allowed to take more time.

Provides a better understanding of stroke systems of care for patients with acute ischaemic stroke.

A multidisciplinary team is required to implement changes, including healthcare professionals and professional organisations.

Extension of the treatment window to 4.5 hours will impact all stages of stroke networks from dispatchers and emergency medicine services to acute stroke units and imaging facilities.

The balance of costs and benefits (in terms of gain in QALYs) favours treatment with rt-PA in the 3-4.5 hour time window after stroke onset vs. non-thrombolytic therapy.

Initial concerns following the publication of ECASS 3, about increasing delays in administration of rt-PA to patients with an acute ischaemic stroke, were not confirmed and in fact the proportion of patients with a door-to-needle time <60 min increased.

ENCHANTED study

The ENchanted Control of Hypertension And Thrombolysis stroke stuDy (ENCHANTED) is an investigator-initiated, randomised, controlled non-inferiority trial, with a 2x2, multi-centre, open label, PROBE design (intention-to-treat, ITT, analysis).1 The study enrolled patients with an acute ischaemic stroke who are eligible for thrombolysis:

The first part of the study (Part A) investigates the efficacy of low-dose intravenous rt-PA (0.6 mg/kg) compared to standard dose rt-PA (0.9 mg/kg), as well as the risk of symptomatic intracerebral haemorrhage (SICH) with either dose;1

Inclusion & exclusion criteria

Patients were included if aged 18 or over, with a clinical diagnosis of acute ischaemic stroke confirmed by brain imaging, who were eligible to receive rt-PA treatment within 4.5 hours of symptom onset.2

Patients that were unlikely to benefit from the intervention due to pre-existing disability (e.g. advanced dementia), with a high risk of mortality within 24 h, or other pre-existing medical illness that may affect outcomes were the main exclusion criteria from the study.2

Primary outcome(for both study arms)1,2

Combined outcome of death or disability (mRS 2-6) at 90 days to determine non-inferiority of low-dose rt-PA vs. standard-dose rt-PA

Key secondary outcomes1,2

Any other ICH, determined on brain imaging within 7 days after treatment

Neurological deterioration from baseline

mRS at 90 days

Other clinical measures, health-related quality of life (HRQoL)

Death

Part A: rt-PA dose

Rationale

rt-PA is currently licensed for use at a dose of 0.9 mg/kg body weight in most countries. In Japan, the licensed dose is 0.6 mg/kg.

Asians appear to have an increased risk of sICH that can be contributed to genetic differences in coagulation and fibrinolysis pathways compared to Caucasians.5

The standard dose of rt-PA has been associated with an increased risk of sICH in Asian patients.6-10

It has been shown that most clots typically dissolve shortly after the injection of rt-PA3, although the infusion lasts for one hour.

Objective

To assess the non-inferior efficacy and safety of low-dose (0.6 mg/kg) intravenous rt-PA with the current standard dose (0.9 mg/kg) rt-PA in patients with an acute ischaemic stroke, randomised within 4.5 hours of onset of symptoms.1,2

Results

3,310 patients (median age of 67, 63% were Asian) were randomised to low-dose rt-PA (n=1607) or standard-dose rt-PA (n=1599).2

The upper limit set for non-inferiority was 1.14, which was exceeded, and thus the trial failed to demonstrate non-inferiority (p=0.51 for non-inferiority).2

Figure 2: Forest plot for the primary outcome, death or disability (mRS 2-6) at 90 days

*adjustment for time from stroke onset to randomisation, score as a continuous measure on the National Institutes of Health stroke scale (NIHSS), age, sex, ethnicity, pre-morbid score of 0 or 1 on the mRS, pre-morbid use of aspirin, other antiplatelet agent or warfarin, and any history of stroke, coronary artery disease, diabetes mellitus and atrial fibrillation.
Adapted from Anderson C, et al. N Engl J Med 2016;374(24):2313-2323. Suppl. DOI: 10.1056/NEJMoa1515510. Presented by Craig Anderson at ESOC 2016, Barcelona, Spain.

Patients treated with low-dose rt-PA had significantly reduced mortality than with standard-dose rt-PA at 7 days (3.6% vs. 5.3%, p=0.02); and at 90 days, (8.5% vs. 10.3%, p=0.07); however, more patients in the standard-dose group had mRS scores of 0-1 compared to the low-dose group (48.9% vs. 46.8% respectively); p=0.04 for non-inferiority of low-dose rt-PA (Figure 3).2

Figure 3: Secondary outcome: unadjusted ordinal shift mRS scores

Major sICH occurred in 1.0% of patients who received the lower dose of rt-PA, and 2.1% of those with the standard rt-PA dose (p=0.01).2

No significant difference was seen in the treatment groups for the occurrence of serious adverse events (p=0.16), but fatal cerebral haemorrhage was increased in the standard dose group vs. the lower dose (2.5% vs. 1.3%, p=0.02).2

Conclusions

ENCHANTED did not achieve its primary objective of showing non-inferiority of low-dose compared to standard-dose rt-PA with respect to death and disability at 90 days.

Standard-dose rt-PA is equally appropriate for Caucasians and Asians.

Low-dose rt-PA was associated with fewer symptomatic intracerebral haemorrhages; however, mortality was not significantly different in the two groups at 90 days.

Part B: blood pressure control

Rationale

Blood pressure (BP) is typically elevated after intracerebral haemorrhage (ICH), and an elevated baseline systolic BP is associated with worse outcomes and an elevated risk of sICH following rt-PA.1

The Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT-2) reported that although the primary endpoint of death and disability was not reduced in patients with spontaneous ICH (within the previous 6h) and elevated SBP with intensive BP-lowering treatment compared to standard treatment, and ordinal analysis shift of the modified Rankin scores did show improved functional outcomes in this group (OR for greater disability, 0.87; 95% CI, 0.77 to 1.00; p=0.04).11,12

Intensive lowering of BP trended towards reduced risk of death or disability, but this did not reach significance (p=0.06). Thus, the benefit of intensive lowering of BP in the hyperacute phase of acute ischaemic stroke remains to be definitively determined.11,12

Objective

To test whether early, intensive lowering of BP (systolic target 130-140 mmHg) displays superior efficacy and reduces risk of any ICH compared to the current guideline recommendation of a systolic target of <180 mmHg.1

Overview

Recruitment of 4800 patients is ongoing (as of November 2016).

Part B has the specific inclusion criteria that subjects have a sustained, elevated BP level of 150 to 220 mmHg, and are able to receive immediate, intensive BP lowering or conservative management of BP levels.

These patients are randomly assigned to either an early, intensive blood pressure regime (systolic blood pressure of <140 mmHg within 1 hour), or a systolic blood pressure of <180 mmHg as per the current guidelines.

All differences were non-significant in univariate analysis. Univariate safety and efficacy outcomes were not different when the CT group was compared to the combined MRI groups.

In multivariate analysis (CT versus all MRI), age and NIHSS entered the model as highly significant predictors for all safety and efficacy outcomes. Only for the primary efficacy endpoint (mRS 0-1 vs. 2-6) an additional variable entered the model: The use of MRI instead of CT increased the odds for a favourable outcome by 34.9%: odds ratio, OR=1.349 (1.041-1.747, p=0.023). For MRI 3h it was 1.558.

Figure 5: Take 5: Safety and efficacy multivariate analysis

Conclusion

MRI-based thrombolysis within and beyond the 3-h time window is at least as safe and possibly more effective than CT-based thrombolysis.

References

Schellinger P, et al. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke 2007;38:2640-2645.

52 patients were randomly assigned to rt-PA and 49 patients to placebo.

Mean age was 71·6 years, and median NIHSS score was 13.

85 of 99 (86%) patients had mismatch of PWI and DWI.

The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with rt-PA and 1.78 with placebo; the median relative infarct growth was 1.18 with rt-PA and 1.79 with placebo.

Reperfusion was more common with rt-PA than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than no reperfusion.

Conclusions

The EPITHET study confirms the results of DEFUSE.

Reperfusion is associated with a better outcome and a reduced infarct growth.

Schellinger P, et al. Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;75:177-185.

SITS-MOST was an observational safety monitoring study from patients on the SITS register, within the EU, Norway, Iceland, and Switzerland, to assess whether intravenous rt-PA, when given as thrombolytic therapy within 3 hours of the onset of ischaemic stroke is as safe and effective in routine clinical practice as reported in randomised controlled clinical trials.

Results

The effect of treatment on modified Rankin scores at 3 months was compared with pooled data from randomised controlled trials (RCTs).

Complete recovery (mRS 0-1) at 3 months was seen in 38.9% (95% CI 37.7-40.1) of SITS-MOST patients compared with 42.3% (37.8-47.0) in RCTs.

The incidence of intracerebral haemorrhage with rt-PA was similar in SITS-MOST and RCTs, when similar definitions of symptomatic intracerebral haemorrhage (sICH) were applied.

Mortality was substantially lower in SITS-MOST (11.3%) than in RCTs (17.3%), and may have been due to the lower age and baseline stroke severity in SITS-MOST.

Summary

Functional independence at 3 months was higher in SITS-MOST (54.8%) than in RCTs (50.1%).

Mortality rates within the first 3 months were lower in SITS-MOST (11.3%) than in RCTs (17.3%).

The results of SITS-MOST confirm that routine use of rt-PA within 3 hours of ischaemic stroke has a safety profile at least as good as that seen in RCTs.

SITS-MOST showed that safety could be maintained across centres, regardless of experience in acute stroke thrombolysis.

SITS-MOST demonstrated that broad implementation of thrombolysis with rt-PA within 3 hours of onset of stroke symptoms in acute ischaemic stroke is as safe and effective as in randomised controlled clinical trials.

Centres participating in the SITS database are required to enter all patients into SITS-ISTR (International stroke treatment register).

Between December 2002 and February 2010, SITS-ISTR looked at a cohort of patients (N=2,376) treated with rt-PA within 3-4.5 hours after the onset of ischaemic stroke and compared the outcome with that of patients treated within the 3-hour time window (N=21,566).

Outcome measures were:

sICH within 24 hours

Mortality

Independence (mRS 0-2) at 3 months

Results

sICH occurred more frequently in patients treated within 3-4.5 hours than in the 0-3 hour group, according to the SITS-MOST definition of sICH (p=0.04), but was not significant for the ECASS II (p=0.35) or NINDS (p=0.66) definitions of sICH.

In the adjusted analysis, the rate of sICH was higher when applying the SITS-MOST and ECASS II definitions (p=0.02 for both), but not for the NINDS definition (p=0.06).

Mortality at 7 days and at 3 months was not significant in the unadjusted analysis (p=0.46 and 0.70 respectively), but was significant at 3 months for treatment within 3-4.5 hours in the adjusted analysis (p=0.005 compared to p=0.052 for mortality at 7 days).

The datasets from many studies investigating risk factors, aetiology, prevalence, ethnic disparity and potential benefits of stroke treatment regimens reside in industry and academic archives long after the studies have been published.

The importance of this stored information is often underestimated.

By collating these datasets, a large and rich pool of information can be utilised for novel analyses of the natural history of homogeneous subgroups of stroke patients.